Abstract Coronary heart disease (CHD) is a leading cause of morbidity and mortality and particularly frequent in type 2 diabetes. Both genetic and environmental factors determine the development of CHD. Recent genome-wide association (GWA) studies have identified several genetic variants for CHD in the general population. It is now a high priority to conduct GWA study for CHD in diabetic patients. In addition, a better understanding of the etiology of CHD requires a careful investigation of intermediate biochemical changes and gene- environment interactions. The Nurses' Health Study (NHS) and Health Professionals' Follow-up Study (HPFS) are well-characterized cohorts whose stored DNA sample and detailed lifestyle information are available. Through a separate NIH grant, we will complete a GWA scan (Affymetrix SNP Array 6.0; ~1 million SNPs) in 3,000 diabetic cases (950 CHD/2,050 non-CHD) from NHS/HPFS by July, 2008. We propose to analyze GWA data with the CHD risk and replicate the top 1200-1400 SNPs in two CHD case-control studies of diabetic patients: Joslin Heart Study (N=1,400) and Costa Rica study (N=890). We will also assess the associations with biochemical risk factors for CHD and examine the gene-environment interactions. The GWA scan, biochemical marker measurement, and collection of detailed information on lifestyle factors have been separately granted. Therefore the proposed project will be extremely cost-efficient. We have assembled a solid group of experienced and committed collaborators with expertise in genetic epidemiology, statistical genetics, bioinformatics, cardiovascular disease, diabetes, and nutrition. We believe that the unprecedented resources available in this project will provide a unique opportunity to identify genetic factors for excessive risk of CHD in diabetic patients.